Clostridium difficile is a Gram-positive, endospore-forming anaerobe that causes life-threatening intestinal infections. C. difficile infections, or CDIs, lead to billions of dollars in healthcare costs and result in over 14,000 deaths per year in the United States alone. C. difficile has been listed by the U.S. Centers for Disease Control and Prevention (CDC) as the highest level threat of antibiotic resistance in the United States. (Office of the Associate Director for Communication, Digital Media Branch, Division of Public Affairs. Antibiotic Resistance Threats in the United States, 2013; Centers for Disease Control and Prevention: Atlanta, Ga., Sep. 16, 2013; http://www.cdc.gov/features/AntibioticResistanceThreats/.) Because C. difficile is a strict anaerobe, the bacterium can survive outside of the host intestine only as a dormant spore. For C. difficile to cause disease, the spores must be ingested. The spores germinate when exposed to bile salts in the intestine, yielding the vegetative form of the bacterium. Once in the vegetative form, C. difficile can produce the toxins that are responsible for disease manifestations. See, for example, Deakin, L. J., et al. Infect. Immun. 2012, 80, 2704; Sorg, J. A.; Sonenshein, A. L. J. Bacteriol. 2008, 190, 2505; Larson, H. E.; Price, A. B. Lancet 1977, 2, 1312; and Bartlett, J. G. Rev. Infect. Dis. 1979, 1, 530.
C. difficile infections are often preceded by the use of therapeutic antibiotics to treat unrelated bacterial infections. (Rupnik, M.; Wilcox, M. H.; Gerding, D. N. Nat. Rev. Microbiol. 2009, 7, 526.) Antibiotic use disrupts the indigenous microbiota, allowing C. difficile to colonize and proliferate within the intestine. Current treatment of CDI typically consists of metronidazole, vancomycin, or, most recently, fidaxomicin. Unfortunately, these antibiotics are not able to treat all CDIs, and recurrence of disease occurs in many patients, especially when infections involve the epidemic 027 isolates. To combat this challenge, new strategies are being explored for the treatment of CDI. See Wilson, K. H.; Perini, F. Infect. Immun. 1988, 56, 2610; Kelly, C. P. Clin. Microbiol. Infect. 2012, 18 (Suppl 6), 21; Comely, 0. A.; Miller, M. A., et al. Clin. Infect. Dis. 2012, 55 (Suppl 2), S 154; Mullane, K. M., et al. Clin. Infect. Dis. 2011, 53, 440; Louie, T. J., et al. New Engl. J. Med. 2011, 364, 422; and Hedge, D. D., et al. Ther. Clin. Risk Manage. 2008, 4, 949.
Host-defense peptides (HDPs) have demonstrated potent activity against pathogenic bacteria and are considered promising candidates for the treatment of bacterial infections. Indeed, the human HDP LL-37 is a potent inhibitor of C. difficile growth. See Zasloff, M. Nature 2002, 415, 389; Boman, H. G. J. Intern. Med. 2003, 254, 197; Hancock, R. E.; Sahl, H. G. Nature Biotechnol. 2006, 24, 1551; McBride, S. M.; Sonenshein, A. L. Infect. Immun. 2011, 79, 167; and Arzese, A., et al. Antimicrob. Chemother. 2003, 52, 375. However, stepwise solid-phase synthesis of peptides is expensive. Synthetic polymers that can mimic the antimicrobial properties of HDPs are attractive because their production should be more facile than that of sequence-specific peptides, and the polymers resist proteolytic degradation. Although a variety of synthetic polymers have recently been examined for inhibition of bacterial growth, there is a long-felt and unmet need for synthetic polymers that inhibit the growth of C. difficile in general and for synthetic polymers that inhibit pathogenic spore outgrowth of C. difficile in particular.